Charcot Marie Tooth disease (CMT) is a rare, inherited and progressive peripheral neuropathy for which no etiological treatment is currently approved. CMT is highly heterogeneous both clinically and genetically. Charcot-Marie-Tooth type 1A (CMT1A) type is autosomal dominant and the most common type of CMT; it is caused, in the vast majority of cases, by a duplication of a fragment of chromosome 17p.11 that includes PMP22. The resulting overexpression of PMP22 is thought to be the main etiological cause of the dysmyelination, of the dysfunction and loss of peripheral nerves and of the muscle wasting that worsen in the course of the disease. Mutations of PMP22 gene, such as modification, deletion or splice mutation, have also been associated with CMT1A. Importantly, dysmyelination of peripheral nerve axons occurs early in postnatal development as was shown in PMP22 transgenic rats [1] and in CMT1A children aged 3.5 years [2]. PXT3003, a combination of (R/S) baclofen, sorbitol and naltrexone has been recently investigated in a one year, randomized, double-blind, placebo controlled phase 2 clinical trial. This trial showed evidence for an improvement beyond stabilization in an adult population of an average age above 40 [3].
Symptoms of CMT1A usually first appear in infancy, generally during the first two decades. Most frequently in the first 10 years, they include clumsiness of gait and deformity of feet. Difficulty in heel walking and areflexia or hyporeflexia of lower limbs are the earliest signs that appear in the children [4]. Symptoms then worsen with time. Molecular studies of PMP22 to diagnose the duplication of this gene remain the most accurate way of diagnosing CMT1A, particularly in young children in whom symptoms are not detectable yet, and also because a significant part of cases are due to a de novo mutation.
As mentioned above, CMT1A is a progressive peripheral neuropathy; by the time peripheral nerve impairment is manifested in adulthood, it may be already irreversible, or poorly reversible. Therapeutic treatment started at this stage of the disease, even if found efficient, cannot modify the early pathological events in the disease development. Accordingly, there is an unmet need for a treatment that would prevent or delay the onset of the disease.